Regioselective preparation of 3-alkoxy-4,5-difluoroanilines by S NAr

Article abstract of DOI:10.1002/ejoc.201201228

A simple and scalable procedure to introduce alcohols selectively at the 3-position of 3,4,5-trifluoroaniline is described. The procedure uses powdered NaOH as base and catalytic 15-crown-5 in refluxing toluene with a Dean-Stark trap. A short exploration of other nucleophiles and fluoroaryl electrophiles is also described.

Full text of DOI:10.1002/ejoc.201201228

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201228
Regioselective Preparation of 3-Alkoxy-4,5-difluoroanilines by SNAr
Sven Van Brandt,[a] Frederik J. R. Rombouts,*[a] Carolina Martínez-Lamenca,[a]
Jos Leenaerts,[a] Tom R. M. Rauws,[a] and Andrés A. Trabanco*[b]
Keywords: Nucleophilic substitution / Aromatic substitution / Fluorine / Arenes
A simple and scalable procedure to introduce alcohols selec-
tively at the 3-position of 3,4,5-trifluoroaniline is described.
The procedure uses powdered NaOH as base and catalytic
15-crown-5 in refluxing toluene with a Dean–Stark trap. A
short exploration of other nucleophiles and fluoroaryl electro-
philes is also described.
Introduction
Nucleophilic aromatic substitution (SNAr) of fluorine[1]
on electron-deficient arenes is well documented and has
been extensively exemplified on fluorobenzenes substituted
by a variety of activating groups such as, for example, nitro,
cyano, sulfonyl, sulfinyl, bromide, keto, or ester groups.[2]
In contrast, the displacement of fluoride on nonactivated
or deactivated arenes has been scarcely reported.[3] Some
procedures include the use of additives,[4] microwave heat-
ing,[5,6] photochemical conditions,[7] as well as high boiling
point polar aprotic solvents such as NMP, DME, or
DMF[3,6,8] and/or addition of cosolvents such as DMPU.[9]
We have recently identified 1,2,4-triazole derivative 1
(Figure 1) as a potent positive allosteric modulator (PAM)
of the nicotinic alpha7 (nACh7) receptor.[10] The compound
contains 3,4-difluoro-5-methoxyaniline (2) as one of the
substituents of the triazole ring, for which a simple and ef-
ficient synthesis suitable for scale-up purposes was required.
Alkoxyfluoroanilines have been traditionally prepared by
SNAr of the corresponding 2- or 4-fluoronitrobenzene fol-
lowed by reduction of the nitro group to the amine [Eq. (1),
Scheme 1], which respectively affords the ortho- or para-alk-
oxy-substituted nitrobenzene as the product.[11] Alterna-
tively, a few examples involving the palladium-catalyzed
amination with ammonia of deactivated alkoxyfluoroaryl
halides have also been reported [Eq. (2), Scheme 1].[12]
Figure 1. Structure of nACh7 receptor PAM 1 (pEC50 = 6.1).
Scheme 1. Reported methods for the preparation of alkoxyfluoro-
anilines.
To the best of our knowledge, SNAr of fluorine with alk-
oxides has never been reported on unprotected fluoroanil-
ines. We present herein the scope and limitations of a gene-
ral, simple, and efficient method for the preparation of alk-
oxyfluoroanilines from commercially available polyfluoro-
anilines.
Results and Discussion
[a] Neuroscience Medicinal Chemistry, Janssen Research and
Development,
Turnhoutseweg 30, 2340 Beerse, Belgium
Fax: +32-16-605344
For the preparation of 3,4-difluoro-5-methoxyaniline (2),
we initially explored the SNAr of commercially available
3,4,5-trifluoroaniline (1a) with sodium methoxide (30 wt.-
% in methanol) under several reaction conditions (Table 1).
Thus, reaction of 1a with NaOMe (5 equiv.) for 8 h under
reflux led to a partial conversion of 1a into 2 (Table 1, en-
try 1). An increase in the number of equivalents of the alk-
oxide (10 equiv.) and prolonged heating (14 h) led to com-
plete consumption of 1a. Unfortunately, the formation of
E-mail: Frombout@its.jnj.com
Homepage: www.janssenpharmaceutica.be
[b] Neuroscience Medicinal Chemistry, Janssen Research and
Development,
c/ Jarama 75, 45007 Toledo, Spain
Fax: +34-925-245771
E-mail: Atrabanc@its.jnj.com
Homepage: www.janssen-cilag.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201228.
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Regioselective Preparation of 3-Alkoxy-4,5-difluoroanilines by SNAr
double-substitution product 4a was also detected in ap- sions and to suppress the formation of isomer 4b (Table 2,
preciable amount (Table 1, entry 2). After further fine-tun- entry 5).
ing of the reaction conditions, we found that heating 1a at
Table 2. Substitution of 3,4,5-trifluoroaniline with benzyl alcohol.
reflux in methanol for 13 h with NaOMe (8 equiv.) gave the
highest isolated yield of 2 (Table 1, entry 3), although the
formation of 4a could not be completely suppressed. Never-
theless, we were pleased to find that the reaction was repro-
ducible and scalable under these optimized reaction condi-
tions, and 2 could be obtained in 77% isolated yield when
starting from 45 g (0.3 mol) of 1a. To broaden the scope of
this simple transformation, we studied the reaction with
other alkoxides as nucleophiles. Initially, we selected benzyl
alcohol for the nucleophilic substitution reaction, as it
would allow diversification upon deprotection of the benzyl
group in a later stage of the synthesis. Because the condi-
tions shown in Table 1 involve the use of the alcohol as the
reaction solvent, they would not be practical for high boil-
ing point alcohols. Therefore, we decided to look for a more
general and equally scalable protocol with the use of benzyl
alcohol as the nucleophile but not as the reaction solvent.
Entry
n
Crown
ether
Base
t
LCMS[a]
Yield 3b[b]
(equiv.) [h] 1a/3b/4b/5b
[%]
1
1.2
1.2
1.02
1.02
1.02
18C6
18C6
18C6
15C5
15C5
KOH (5) 0:73:0:23
3
n.d.[c]
56[e]
67
2
NaOH (5) 18 10:68:16:6[d]
3[f]
4
NaOH (2) 18
NaOH (2)
NaOH (2)
3:79:0:14
15:81:0:4
5
5
67
5[g]
0:46:27:27[d]
n.d.[c]
Table 1. Nucleophilic substitution of 3,4,5-trifluoroaniline (1a)
with NaOMe.
[a] Conversion of 1a as determined by LC–MS analysis of the crude
reaction mixture. [b] Yield of isolated 3b in reactions performed
with 10 g of 1a. [c] n.d.: not determined. [d] GC–MS was used to
determine relative ratio. [e] 3b:4b = 4:1. [f] A reaction with 250 g of
1a led to the isolation of 3b in 53% yield. [g] Performed with 2 g
of 1a without the use of a Dean– Stark trap.
These optimized conditions were selected to extend the
scope of this nucleophilic substitution with a diverse set of
primary and secondary alcohols (i.e., 6a–j). The results ob-
tained can be found in Table 3. Primary alcohols 6a–e and
secondary alcohol 6f afforded corresponding substitution
products 7a–f in moderate to good yields (47–82%; Table 3,
entries 1–6). Tertiary tert-butyl alcohol 6g was unreactive
under these conditions and even so when sodium tert-but-
oxide was used as the base (Table 3, entry 7). Unfortunately
Entry
n
1a [g]
t [h]
LCMS[a] Yield 2[b]
1a/2/4a
[%]
1
2
3
5
10
8
4
4
45
8
14
13
27:56:0
0:72:28
7:78:15
n.d.[c]
60
77
[a] Based on UV trace in LC–MS. [b] Yield of isolated product.
[c] n.d.: not determined.
For this we envisaged the use of nonprotic solvents com- an aromatic alcohol, such as phenol (6h), failed to give the
bined with additives with the aim to enhance the reactivity substitution product 7h (Table 3, entry 8). Interestingly, the
of the alkoxide in the reaction media. After initial screening reaction was compatible with tertiary amine 6i and primary
of the solvents and additives, we found that heating a mix- amine 6j (Table 3, entries 9 and 10).
ture of 1a, benzyl alcohol (1.2 equiv.), and potassium hy-
The use of nitrogen nucleophiles was also studied. Thus,
droxide in toluene at reflux in the presence of 18-crown-6 different N-nucleophiles 6k–n were selected for the reaction
(18C6) led to the formation of a 3:1 mixture of 3b/5b with 1a. The results obtained are summarized in Table 4.
(Table 2, entry 1). The formation of the double-substitution
Benzamide 6k and imidazole 6l[6] failed to produce the
product 5b could be suppressed by using NaOH instead of corresponding substitution products 7k and 7l under stan-
KOH as the base; however, the formation of 3b was then dard reaction conditions (Table 4, entries 1 and 2). Interest-
accompanied by regioisomer 4b in 4:1 ratio (Table 2, en- ingly, trace amounts of substitution products 7m and 7n
try 2). The formation of para-substituted product 4b was were observed for piperazine 6m and morpholine 6n under
avoided by decreasing the number of equivalents of NaOH the same reaction conditions. Better conversions towards
(from 5 to 2) and BnOH (from 1.2 to 1.02), and 3b was 7m (47%) and 7n (46%) were obtained by using amines 6m
finally obtained in a satisfactory isolated yield of 67% an 6n as the solvent while heating the reaction mixture at
(Table 2, entry 3). Finally, the switch to 15-crown-5 (15C5), 180 °C in a sealed tube (Table 4, entries 3 and 4).
which is known to be a better coronand for sodium, ac-
Finally, the scope of the arene electrophile was also
celerated the reaction and reduced the reaction time to 5 h studied. For this, fluorobenzenes 1b–h were treated with
(Table 2, entry 4). Of note is that all reactions were per- benzyl alcohol. The reactions were performed under the op-
formed with the use of a Dean–Stark trap for azeotropic timized reaction conditions described above (1.02 equiv.
removal of the water formed during the course of the reac- BnOH, 2 equiv. NaOH, 0.02 equiv. 15C5, toluene, reflux/
tion. This was found to be essential to achieve high conver- Dean–Stark).
Eur. J. Org. Chem. 2012, 7048–7052
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7049

F. J. R. Rombouts, A. A. Trabanco et al.
SHORT COMMUNICATION
Table 3. Substitution of 3,4,5-trifluoroaniline with various alk-
oxides.[a]
Table 4. Substitution of 3,4,5-trifluoroaniline with nitrogen nucleo-
philes.[a]
[a] The reactions were carried out with 2 g of 1a. [b] Isolated yield.
[c] n.r.: no reaction, only self-condensation of 1a was observed by
LC–MS analysis of the reaction crude. [d] Conditions A: 1a
(1.02 equiv.), 6k–n (2 equiv.), NaOH (0.02 equiv.), 15-crown-5, tol-
uene, reflux (Dean–Stark), 18 h; Conditions B: 1a, amine 6m–n
(solvent), sealed tube 180 °C, 18–36 h.
reacted smoothly to afford substitution products 8b and 8bЈ
in 35 and 16% yield, respectively (Table 5, entry 1). This
yield, which is lower than that obtained in the reaction of
1a, can be explained by the low boiling point of 1b
(94.5 °C), as 1b may slowly evaporate during the course of
the reaction.[13] 3,5-Difluoroaniline (1c) gave substitution
product 8c in slightly higher yield (44%; Table 5, entry 2),
although an extended heating time of 18 h was required (vs.
5 h for 1a), which indicates that the para-fluoro substituent
plays an important activating role in the reaction. Interest-
ingly no selectivity was found with 3,4-difluoroaniline (1d),
which led to the isolation of 8d as a 1:1 mixture of the
3- and 4-substitution products (Table 5, entry 3). Simple 4-
fluoroaniline (1e), lacking the double meta-fluorine substi-
tution, gave with very low conversion and isolated yield ex-
pected product 8e (Table 5, entry 4). To our delight, both
anisole 1f and dimethylaniline 1g gave high-yielding conver-
sions to their respective meta-substituted products 8f and
8g. Surprisingly, 2,3,4-trifluoroaniline (1h) gave only ortho-
and para-substitution products 8h and 8hЈ in 49 and 15%
yield, respectively (Table 5, entry 7)[14] without a trace of
meta-substituted difluoroaniline. When comparing the
[a] The reactions were carried out with 2 g of 1a. [b] Isolated yield.
[c] n.r.: no reaction.
The results of this exploration are shown in Table 5. selectivity observed for 1a (preferentially meta) with that for
1,2,3-Trifluorobenzene (1b), which lacks the amino group, 1d (1:1 meta/para) with benzyl alcohol, it appears the SNAr
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Regioselective Preparation of 3-Alkoxy-4,5-difluoroanilines by SNAr
is mostly dictated by the relative rate factors of ortho- and
meta-fluorine substitution (fo-F = 60 vs. fm-F = 180) rather
than the mesomeric effect of the aniline.[15] In contrast, the
preferred ortho-substitution of 1g is in line with previously
observed selectivity for xantates and thiolates and can be
similarly explained by precoordination of the aniline to the
attacking nucleophile.[16] Moreover, as expected, the reactiv-
ity appears to be highly controlled by the number of fluor-
ine substituents present.
Conclusions
3-Alkoxy- and 3-aminodifluoroanilines are easily access-
ible through simple nucleophilic aromatic substitution of
3,4,5-trifluoroaniline with oxygen and nitrogen nucleo-
philes. The developed conditions have proven to be unex-
pectedly mild and easily scalable, which allows the prepara-
tion of useful building blocks on a scale up to 250 g.
Furthermore, the reported transformations are remarkable,
because they depend less on mesomeric deactivation of the
aniline than on the relative rate factors of substitution, and
precoordination of the aniline when possible. This results
in meta selectivity for the 3,4,5-trifluoroanilines but in
ortho/para selectivity for 1,2,3-trifluoroaniline. Extending
the scope of the reaction with both substrate and nucleo-
phile showed trends confirming the above-mentioned hy-
pothesis. As expected, more bulky and/or less-reactive nu-
cleophiles led to lower yields, whereas more electron-rich
substrates reacted smoothly. Similarly, higher fluorination
of the arene led to higher reactivity and yields.
Table 5. Substitution of fluorobenzenes 1b–h with benzyl alcohol.[a]
Supporting Information (see footnote on the first page of this arti-
1
cle): Full experimental details and copies of the H NMR and 13C
NMR spectra.
Acknowledgments
We thank Tom Govaerts and Corina Janssen for performing the
scale-up reaction to 250 g. We also thank Michel Carpentier for
providing the high-resolution mass spectra.
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F. J. R. Rombouts, A. A. Trabanco et al.
SHORT COMMUNICATION
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Published Online: November 15, 2012
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